PROJECT ABSTRACT Chronic inflammatory diseases, such as inflammatory bowel disease (IBD), are a significant socio-economic problem with an accelerating incidence around the world that affects adolescents and young adults. These diseases manifest with chronic dysregulated immune responses that ultimately promote tissue destruction. While most current therapeutic approaches are focused on limiting inflammation, there is an urgent need to develop novel strategies that also facilitate tissue repair and mucosal healing. The fundamental focus of this research proposal is to mechanistically define a novel pathway that promotes mucosal healing in the intestine, and further determine its therapeutic potential in preclinical mouse models. In our preliminary data, we unexpectedly identified that hepcidin, the master regulator of systemic iron homeostasis in mammals, is an essential promoter of mucosal healing in the intestine. Surprisingly, hepatocytes were not the critical cellular source of hepcidin in this context, but rather we identified that dendritic cells (DCs) express hepcidin in response to microbial simulation. Further, we identified that DC-derived hepcidin support mucosal healing by regulating local iron levels and modulating the composition of the intestinal microbiota. These findings provoke the central hypothesis that DC-derived hepcidin is a critical regulator of mucosal healing. We will employ theses approaches and develop innovative tools to define the role and regulation of DC-derived hepcidin during homeostasis or following intestinal damage and inflammation. Three specific aims of this project will determine (i) What DCs express hepcidin and how is DC-derived hepcidin regulated to promote mucosal healing? (ii) How does DC-derived hepcidin mechanistically influence mucosal healing? and (iii) Can hepcidin be therapeutically harnessed to support mucosal healing? Collectively, these studies will mechanistically define the role and regulation of DC-derived hepcidin in basic mouse models and human samples. Further, the proposed studies will provide important pre-clinical evidence on the therapeutic potential of modulating DCs or hepcidin in the context of IBD and other chronic inflammatory diseases.